Final PMB definition guideline: Endometrial cancer

1 | P a g e PMB definition guideline: Endometrial cancer
Final PMB definition guideline: Endometrial cancer
Published date: 15 April 2019
Review due: 15 April 2021
Disclaimer:
The endometrial cancer benefit definition has been developed for the majority of standard patients. The benefit definition is subject to the provisions of Regulations 15H and 15I. The benefit definition does not describe specific in-hospital management such as theatre, anaesthetists, anaesthetist drugs and nursing care. However, these interventions form part of care and are prescribed minimum benefits. .
Acknowledgements
The Council for Medical Schemes (CMS) would like to acknowledge all stakeholders who assisted in drafting this document, including gynecologists and obstetricians, oncologists, pathologists, radiologists, patient advocacy groups, funders and administrators.
The CMS would like to acknowledge the following clinical experts for their insights during the drafting of the document: Dr Angelique Coetzee, Dr Anthony Levy, Dr H-T Wu, Dr Kamedran Govender, Dr Kasandri Govender, Dr Rene Krause, Dr Setheme Mosehle, Dr Sheynaz Bassa, Dr Shilendra Hariparsad, Professor Leon Snyman and Professor Paul Ruff.
The CMS would also like to thank the following individuals comprising of representatives from patient advocacy groups, the South African Medical Association (SAMA), pharmaceutical companies, medical aid funders and administrators, who were members of the clinical advisory committee set up to discuss member entitlements for cervical cancer, for their valuable contributions: Dr Abongile Qamata (Medscheme) , Dr Jo Samsonowicz (Medscheme), Dr Sandile Mhlongo (Discovery Health ), Ms Arlene Anderson (Janssen Pharmaceutical), Ms Kim Cardwell (Discovery Health), Ms Shelley-Ann McGee (SAMA) and Professor Manie de Klerk (MMI).
The CMS would also like to acknowledge the following individuals for their assistance in the compilation of this document: Professor Nathaniel Mofolo, Professor Shinga Feresu, Dr Edith Madela-Mntla, and Dr Zinhle Makatini.
Abbreviations
IV Intravenous therapy
Table of Contents
1. Introduction ................................................................................................................................... 6
3. Epidemiology and burden of disease .................................................................................................. 7
4. Screening of endometrial cancer ......................................................................................................... 7 5. Diagnosis .......................................................................................................................................... 8
5.1 Consultations ........................................................................................................................ 8
5.2 Histopathology ....................................................................................................................... 8
6.2 Imaging radiology for staging endometrial cancer .................................................................. 12
7.1 Surgical management ........................................................................................................... 12
References .......................................................................................................................................... 18
1. Introduction
1.1. The legislation governing the provision of the prescribed minimum benefits (PMBs) is contained in the Regulations enacted under the Medical Schemes Act, 131 of 1998 (the Act). It has been noted however, that in respect of some of the diagnosis treatment pairs (DTPs), medical scheme beneficiaries sometimes find it difficult to know their entitlements in advance. Medical schemes also interpret these benefits differently, resulting in a lack of uniformity of benefit entitlements.
1.2. The benefit definition project is coordinated by the Council for Medical Schemes (CMS), and aims to define the PMB package as well as to guide the interpretation of the PMB provisions by relevant stakeholders.
2. Scope and purpose
2.1. This document serves as a recommendation for the diagnosis, treatment and care of individuals with endometrial cancer, in any clinically appropriate setting as outlined in the Act.
2.2 The purpose is to improve clarity in respect of funding decisions by medical schemes, taking into consideration evidence based medicine, affordability, and in some instances cost-effectiveness.
Table 1: Possible ICD10 codes for identifying endometrial cancer
ICD 10 code WHO description C54.1 Malignant neoplasm, endometrium C54.3 Malignant neoplasm, fundus uteri C54.8 Malignant neoplasm, overlapping lesion of corpus uteri C54.9 Malignant neoplasm, corpus uteri, unspecified C55 Malignant neoplasm of uterus part unspecified D07.0 Carcinoma in situ, endometrium Other applicable codes C57.0 Malignant neoplasm, fallopian tube C57.1 Malignant neoplasm, broad ligament C57.2 Malignant neoplasm, round ligament C57.3 Malignant neoplasm, parametrium C57.4 Malignant neoplasm, uterine adnexa, unspecified C54.2 Malignant neoplasm, myometrium
2.3 The CMS acknowledges that some patients will not qualify for PMB entitlements under the definition of treatable cancers as outlined in explanatory note 3, annexure A of the Act. In these instances, when the treatment intent is no longer curative, DTP 260S, may be applied depending on the clinical case.
Table 2: Applicable PMB code for a non-curative setting in endometrial cancer
PMB Code PMB Description ICD10 Code ICD10 Description
260S # Imminent death regardless of diagnosis
# Comfort care; pain relief; hydration
Z51.5 Palliative care
3. Epidemiology and burden of disease
3.1 Endometrial cancer is a cancer that arises from the endometrium (the inner lining of the uterus) and is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body (Kong, 2014).
3.2 Endometrial adenocarcinoma occurs during the reproductive and menopausal years. Most women with endometrial cancer are aged between 65-74 years with a median age of 70 years. Approximately 5% of women younger than 40 years have adenocarcinoma, and 20-25% of women are diagnosed before menopause (Creasman, 2017; NCI 2012).
3.3 In 2015, there were 455 000 incident cases of uterine cancer worldwide with 90 000 deaths. In South Africa, uterine cancer is ranked the 16th most common cancer and ranked 20th by the number of deaths.
3.4 Unlike most cancers, the number of new cases has risen in recent years, including an increase of over 40% in the United Kingdom between 1993 and 2013 [Galaal, 2014]. Some of this rise may be due to the increase in obesity rates in developed countries [Vale 2012], increasing life expectancies, and lower birth rates [Hoffman 2012].
3.5 Endometrial cancer is more common in developed countries, where the lifetime risk of endometrial cancer in people born with uteri is 1.6%, compared to 0.6% in developing countries [Galaal 2014, WCRI 2014]
3.6 Endometrial carcinoma is a less common gynaecological malignancy in the developing world, yet a significant number of individuals are diagnosed each year in South Africa [Botha 2009]. The relative frequency of endometrial carcinomas has increased over the last years in developing economies due to an increase in obesity and a decrease in fertility rate [Botha 2009].
3.7 The most common histological type is endometriod-type adenocarcinoma but other histological types include mucinous adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma (UPSC), squamous carcinoma and also carcinosarcoma [Botha 2009, CANSA 2012, Singh 2015].
4. Screening of endometrial cancer
4.1 There is no evidence (Smith, 2001) nor validated tests (Leslie, 2012) to support the screening of asymptomatic women, with the exception of those who have or are at increased risk of Lynch syndrome (Smith, 2001).
4.2 The early clinical presentation and high early detection rate of 85%, make it unlikely that screening will have a successful impact on earlier detection and increased survival rate. (National Cancer Institute, 2016).
4.3 Screening for endometrial cancer is therefore not recommended as PMB level of care.
5. Diagnosis
5.1 Consultations
5.1.1 The approach to initial evaluation for suspected endometrial cancer should involve the history and physical examination, endometrial biopsy and determination of the histopathologic subtype.
5.1.2 Vaginal bleeding is the most common clinical presentation of endometrial cancer in postmenopausal women (Sorosky et al, 2012) and as such all postmenopausal bleeding should be investigated, especially if risk factors for endometrial hyperplasia or cancer are present.
Table 3: Recommended consultations for the diagnosis, staging and risk assessment of endometrial cancer
Treating provider Number of consultations GP or physician 1 Specialist (Gynaecologist / Gynaecology oncologist / Oncologist/ Surgeon)
4
5.2.1. The definitive diagnosis of endometrial cancer requires an endometrial tissue sample (Saso, 2011). Histological information obtained from the endometrial biopsy is deemed sufficient for planning definitive treatment (McCluggage, 2006 & McKenney, 2009). Persistence of symptoms following a negative initial assessment results warrants further diagnostic evaluation.
Table 4: Recommended PMB level of care histopathology for endometrial cancer
Description Immunohistochemistry
Endometrial biopsy
5.2.2. Pathological diagnosis is standard for evaluation of the endometrial cavity. World Health Organisation (WHO) classifies endometrial carcinoma in seven different types – endometroid carcinoma, mucinous adenocarcinoma,
serous carcinoma, clear cell carcinoma, neuroendocrine carcinoma, mixed carcinoma, undifferentiated and dedifferentiated carcinoma (Kurman et al, 2014)
5.2.3. Based on differences in both endocrine and metabolic factors (Bokman 1983), two distinct histological categories of adenocarcinomas of the endometrium, type I and type II are recognised (Sorosky, 2012). Type I is the most common form, representing more than 70% of cases and are associated with unopposed estrogen stimulation with high rates of K-ras and PTEN loss and defects in mismatch repair genes resulting in microsatellite instability. Type 1 generally have a favorable prognosis (Practice Bulletin, 2015).
5.2.4. Type II tumors which consist of higher grade adenocarcinomas and non-endometroid histologies, have a tendency for deep invasion of the endometrium. They carry a poor prognosis as well as having a high risk of relapse and metastasis. Although type II tumours accounts for 10% endometrial cancers, they are associated with 40% of related deaths (Sorosky, 2012).
5.2.5. Serous carcinomas as considered prototypes 2 and are characterised by the p53 mutations. However, some cases remain morphologically ambiguous, indeterminate or hybrid adenocarcinomas and require immunohistochemistry (p53, PTEN) and mutational analysis to allow for an accurate work up. Clear cell carcinomas represent a heterogeneous group of tumours with intermediate features between type I and type II.
5.2.6. As endometrial cancer is considered high-risk if it is grade 2 or 3 disease and there is evidence of clear cell or papillary serous histology, further imaging by abdominal-pelvic MRI or CT scan should therefore be reserved for women with high risk histology types (e.g. grade 3 endometrioid endometrial cancer, uterine serous cancer, clear cell cancer). (Francis et al, 2009)
5.3. Diagnostic procedures
5.3.1 For patients with abnormal or post-menopausal bleeding, work up may involve hysteroscopy combined with Dilation and curettage (D&C) to gain additional information regarding benign processes causing bleeding. Hysteroscopy may be helpful in evaluating the endometrium for lesions, such as polyp, if the patient has persistent or recurrent undiagnosed bleeding (Gimpelson, 1988)
Table 5: Diagnostic procedures recommended as PMB level of care
Description Endometrial biopsy
Cervical biopsy
5.4. Laboratory Investigations
5.4.1. Although there are no specific laboratory tests for the evaluation of endometrial cancer, preoperative investigations should include a full blood count, renal panel, urea and electrolytes and liver function tests (Baekelandt et al, 2008, Creasman et al, 2007).
5.4.2. Prothrombin time and partial thromboplastin time may also be considered for patients with heavy bleeding.
Table 6: Recommended PMB level of care laboratory investigations for endometrial cancer
Description Comment Full Blood Count (FBC) including platelets
Initial preoperative evaluation.
Initial preoperative evaluation.
Prothrombin time (PT) and partial thromboplastin time (PTT)
Not routine. May be required for patients with heavy bleeding
CA125 Helpful in monitoring clinical response in patients with extrauterine disease.
5.5. Imaging
5.5.1. Depending on access, histologic endometrial evaluation and transvaginal ultrasound are the preferred initial diagnostic evaluations for patients with suspected endometrial cancer. The recommendation of either transvaginal ultrasonography or endometrial biopsy being performed as the initial work-up for the evaluation of endometrial cancer is reflected in most guidelines (Saso, 2011).
5.5.2. Transvaginal ultrasound measures the endometrial thickness and discriminates between benign and malignant endometrium. Because of its high sensitivity, a transvaginal ultrasound (TVS) is often the diagnostic tool of choice when evaluating for endometrial cancer (Khathi, 2014). Persistence of bleeding despite a normal transvaginal ultrasonography result, warrants a tissue biopsy (Sorosky, 2012).
5.5.3. Imaging tools such as CT, MRI, and/or PET/CT are not recommended as PMB level of care in the diagnostic stage but have a role in the staging and risk assessment of endometrial cancer. These may be used to assess disease extent and to evaluate for metastatic disease as indicated based on clinical symptoms, physical findings, or abnormal laboratory findings (Lee et al, 2011, Ortesh et al, 2008, Antonsen et al, 2013).
5.5.4. Chest X-ray is recommended as a tool to rule out pulmonary metastasis and should be the work up package for initiation assessment (Pecorelli, 1999).
Table 7: Recommended PMB level of care imaging radiology for diagnosis and work-up of endometrial cancer
Description Comment Ultrasound: abdominal / pelvic Transabdominal sonography is the preferred technique for
evaluation of endometrial disorders and is especially useful in the workup of abnormal uterine bleeding.
Transvaginal ultrasound Initial study for the evaluation of endometrial cancer.
Chest x-ray If abnormality is detected, then chest imaging is recommended.
Ultrasound abdomen and chest
PET – CT
CT chest
6. Staging and risk assessment
6.1.1 Endometrial carcinoma is surgically staged according to the joint 2010 International Federation of Gynecology and Obstetrics (FIGO)/TNM classification system (Creasman, 2009) This staging system has been found to be highly prognostic in the case of endometrioid tumors (Lewis, 2009) The most important prognostic factors identified in endometrial carcinoma are the FIGO stage, histological subtype, grade, depth of myometrial invasion, lymphovascular space invasion (LVSI), and age (Colombo, 2016).
6.1.2 The staging streamlines stages I and II of endometrial cancer. Stage I is now less than 50% of myometrial invasion and stages IB being 50% of more of myometrial invasion. (Creasman, 2009) Stage II only involves patients with cervical stromal invasion whilst stages IIIC is divided into IIIC1 and IIIC2 given worse survival with paraortic nodes. (Creasman, 2009)
6.1.3 Traditionally surgical staging has been accomplished with open laparotomy, but minimally invasive techniques are increasingly getting widely accepted. A number of studies have demonstrated feasibility of a laparoscopic approach (Walker, 2006, Humprey, 2009 & Palamba 2009).
6.2 Imaging radiology for staging endometrial cancer
6.2.1. CT although not routinely recommended for evaluation of most endometrial carcinoma, could be useful in further preoperative work up of papillary serous tumours or more aggressive histological types (Spencer et al, 2008).
6.2.2 Contrast enhanced MRI can be of use in assessment if locoregional extension in the pelvis is clinically indicated (Baekelandt et al, 2008). MRI can identify patients at highest risk of metastatic disease (Spencer et al, 2008, Frei et al, 2000).
Table 8: Recommended PMB level of care imaging radiology for staging and risk assessment of endometrial cancer
Description Comment
CT chest Chest imaging without contrast is recommended for staging
CT abdomen and pelvis For high grade carcinoma, may be used to assess disease extent and evaluate metastatic disease based on clinical symptoms or pathology findings. (Ortashi et al, 2008, Kitajima et al, 2011)
MRI abdomen and pelvis In patients who are inoperable to plan radiotherapy. Clinical criteria to be defined
PET – CT On motivation for patients who are undergoing surgery
7. Treatment options for endometrial cancer
7.1 Surgical management
7.1.1 Endometrial cancer is treated primarily with a comprehensive surgical staging operation, which is usually curative and includes hysterectomy (abdominal, vaginal, or minimally invasive), bilateral salpingo-oophorectomy, abdominopelvic washings, lymph node evaluation and pelvic and para-aortitic lymph nodes dissection (Kong et al, 2010; Creasman, 2015; Lachance et al, 2008; Sonoda, 2014, Volpi et al., 2005, Zullo et al., 2005).
7.1.2 It is sometimes difficult to distinguish primary cervical cancer from endometrial cancer with cervical involvement. A radical hysterectomy is recommended as PMB level of care and should be considered for the cases with stage II endometrial cancers (Takano et al, 2013).
7.1.3 With increasing surgeon experience and a corresponding increase in detection rate of 90% or greater, combined with a decrease in false-negative rates, sentinel lymph node mapping can play a more prominent role in lymph node assessment and staging in early-stage of endometrial cancer (Nadeem & Abu-Rustum, 2014)
7.1.4 Patients with high-risk histological subtypes of endometrial cancer such as clear cell and papillary serous adenocarcinomas should receive full staging surgery that includes pelvic and/ or para-aortic lymphadenectomy and omentectomy (Giede et al, 2013).
7.1.5 If the cancer has spread throughout the pelvis and abdomen, a debulking procedure (removal of as much cancer as possible) may be done (American Cancer Society, 2016).
7.1.6 Advanced disease patients may be treated with maximal surgical cytoreduction (Creasman, 2015). 7.1.7 Multiple studies have addressed the potential benefits of the excision of secondary lesions on overall survival in
patients with recurrent endometrial cancer (William et al, 2014). 7.1.8 Laparoscopic hysterectomy is recommended as PMB level of care subject to the use of the following surgical
equipment. This is to ensure that the costs of disposables used for the procedure make this procedure cost effective and affordable.
Table 9: Recommended basket for laparoscopic hysterectomy
Disposable instruments
1xoptic standard port 5/10/11/12 3x5mm ports Sutures: PDS/Vicryl/V-lock/J-needle/ Vicryl Rapid skin/Monocril Ligasure/harmonic scalpel/Thunderbeat/or other Bipolar Device Foleys catheter
Reusable instruments Suction and irrigation Graspers and needle holders Bipolar forceps and cable Monopolar cable Uterine manipulator with colpotomy cuff / VCare Plus
Table 10: PMB Level of care for surgical management of Endometrial Cancer
Description
Salpingo-oophorectomy (unilateral or bilateral)
Total laparoscopic hysterectomy
Debulking surgery
Peritoneal lavage
7.2 Chemotherapy
There is no general agreement as to what constitutes the best chemotherapy, as very few phase III studies have been done comparing different chemotherapy regimens (Creasman, 2017). As a result, cytotoxic chemotherapy has a limited place in the management of advanced or recurrent endometrial cancer (Humber et al, 2007). Multi-agent chemotherapy regimens are preferred over single agents, if tolerated (NCCN, 2016).
7.2.1 Adjuvant 7.2.1.1 For patients with stage III or stage IV disease and for those with recurrent endometrial cancer, the prognosis remains
poor and the optimal adjuvant therapy is yet to be established. However, a subset of these patients may benefit from hormonal manipulation, systemic chemotherapies, or combination treatment with volume-directed radiotherapy and systemic chemotherapy.
7.2.1.2 Docetaxel may be considered for patients in whom paclitaxel is contraindicated (NCCN, 2016). 7.2.1.3 Salvage agents such as paclitaxel may be an option for second-line therapy in patients who have disease recurrence
even after first-line chemotherapy (Creasman, 2017).
7.2.2 Metastatic 7.2.2.1 For patients with recurrent or metastatic disease, rates of response to multi-agent chemotherapy are as high as 50%
to 60%. However, cures with chemotherapy alone are rare (Eifel, 2013). 7.2.2.2 Adjuvant postoperative treatment recommendations in advanced stage disease are widely disparate and an area of
active research (Kumar, 2015).
7.2.2.3 Advanced, metastatic or recurrent endometrial carcinoma presents a difficult management problem (Humber et al, 2007; Moxley, KM & McMeekin, 2010). The platinum and anthracycline compounds have been widely used for many years, but their impact on progression-free survival (PFS) and overall survival (OS) is not clear. The addition of anthracyclines (e.g. doxorubicin) or the taxanes [e.g. paclitaxel] to cisplatin increases the response rate. However, while more intensive regimens are associated with the gain in survival, grade 3 and 4 myelosuppression and gastrointestinal toxicity are also increased (Humber et al, 2007, Tirmazy et al., 2014).
7.2.2.4 The effectiveness of progestational agents has been theorised to increase with the use of estrogenic compounds, such as tamoxifen, which have been documented to increase progesterone receptors (PgRs) in human endometrial cancers. While hormone therapy as an adjuvant treatment is not recommended, for advanced or recurrent disease, oral medroxyprogesterone acetate showed an overall response rate of 25%, and patients with well-differentiated tumours and positive progesterone receptor status had an even higher response rate, particularly with tamoxifen combined with medroxyprogesterone acetate (Plataniotis, G. & Castiglione, M. 2010).
Table 11: Recommended chemotherapy for endometrial cancer
Indication Active ingredient/s Comment (when necessary)
Adjuvant Doxorubicin Cisplatin Carboplatin Paclitaxel
Docetaxel may be considered for patients in whom…

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